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Synthesis of 1,3,5-Triazines via Cu(OAc)2-Catalyzed Aerobic Oxidative Coupling of Alcohols and Amidine hydrochlorides Qing You, Fei Wang, Chaoting Wu, Tianchao Shi, Dewen Min, Huajun Chen, Wu Zhang* Abstract: Cu(OAc)2 was found to be an efficient catalyst for dehydrogenative synthesis of 1,3,5-triazine derivatives via oxidative coupling reaction of amidine hydrochlorides and alcohols in air. Both aromatic and aliphatic alcohols can be involved in and thirty-three products were obtained with good to excellent yields. Moreover, the use of ligand, strong base and organic oxidant is unnecessary.
Introduction 1,3,5-triazines are very important skeletons of many biologically active compounds, such as herbicides, insecticides, fungicides, anticarcinogens and antivirals (Figure 1).1 In addition, they are also widely used as organic dyestuff, liquid crystal, flourescent brightener, electroluminescent materials, gas generating agent, solid propellant and pyrotechnics.2–3 In the past decades, a few approaches, including transition metal-catalyzed coupling reaction of halogenated 1,3,5-triazines,4 the cycotrimerizations of nitriles5 and multicomponent reaction of cyanamid, 1,2,4-triazole and triethyl orthoformate have been developed for the synthesis of 1,3,5-triazine derivatives.6 Alternatively, these compounds were also obtained through the pathways based on the use of available amidines as substrates, for example, domino heterocyclization of isothiocyanates with aryl amidines,7 cesium carbonate-promoted cyclodehydrogenation of amidine hydrochloride with aromatic aldehyde.8 However, these methods suffer from limitations of operating difficulties or tough reaction conditions involving strong base, microwave, noble metal catalyst and organic oxidant. Recently, Zhang et al. reported new strategies for the synthesis of 2,4,6-triaryl-1,3,5-triazines based on ruthenium-catalyzed reaction of aryl methanols and amidines.9 The disadvantages of the strategy lies in noble metal ruthenium-based catalysts and limitation of substrate suitability. As a result, more robust and efficient method for the synthesis of 1,3,5-triazine is still extremely in demand, especially involving the synthesis carried out under gentle conditions with inexpensive catalysts. Copper catalysts with features of low cost and environmental friendliness were frequently utilized to synthesize novel heterocyclic compounds.10–12 For example, Nagasawa et al. have reported that Cu(OTf)2 exhibited impressive catalytic ability in intramolecular oxidative C–N coupling reaction and
Figure 1. Parts of Products of 1,3,5-Triazines Previous report:
This work:
Scheme 1. Synthesis of 1,3,5-Triazines intermolecular amino cyclization.13 Our previous findings also showed that copper-based catalysts are attractive in the catalytic formation of carbon–heteroatom bonds (Scheme 1).14 Herein, we report the synthesis of 1,3,5-triazine derivatives directly by oxidative coupling of amidine hydrochlorides and alcohols in air with Cu(OAc)2 as a catalyst. Compared with the relevant reported reactions for the synthesis of 1,3,5-triazine derivative,8,9 our method is more efficient as evidenced by the fact that both aryl methanols and alkyl alcohols are utilizable as starting reactants in the oxidative coupling reaction.
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Table 1. Optimization of the Reaction Conditionsa
entry
catalyst (mol%)
ligand
solvent
base
1 2
nanoCuO (5) CuCl2 (10)
Phen Phen
toluene toluene
K2CO3 K2CO3
yield (%)b 85 75
3
Cu(NO3)2 (10) Cu(OAc)2 (10) Cu(acac)2 (10) Cu(OTf)2 (10) Cu(OAc)2 (5) Cu(OAc)2 (15) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10)
Phen
toluene
K2CO3
70
Phen
toluene
K2CO3
88
Phen
toluene
K2CO3
80
Phen Phen Phen
toluene toluene toluene
K2CO3 K2CO3 K2CO3
85 60 89
toluene
K2CO3
88
toluene
NaHCO3
87
_
toluene
Na2CO3
88
_
toluene
_
_
_
DMF
Na2CO3
45
_
DMSO
Na2CO3
55
_
toluene
Na2CO3
30
_
toluene
Na2CO3
60
_
toluene
Na2CO3
55
_
toluene
Na2CO3
70
_
toluene
Na2CO3
80
4 5 6 7 8 9 10 11 12 13 14 15c 16d 17e 18f 19g
_ _
a Reaction conditions: benzamidine hydrochloride (1 mmol), benzyl alcohol (0.6 mmol), Cu(OAc)2 (10 mol %), Na2CO3 (1 mmol), toluene (2.5 mL) under reflux in air for 24 h. bIsolated yield. Reaction temperature: c80 oC, d100 oC. Reaction time: e6 h, f12 h, g18 h.
Results and discussion We started with the optimization of the oxidative coupling conditions exploiting benzyl alcohol (1a) and benzamidine hydrochloride (2a) as the model substrates. The results obtained
DOI: 10.1039/C5OB00724K
from screening of the copper catalysts, ligands and solvents are summarized in Table 1. Given efficient catalytic activity and good recyclability of CuO nanoparticles,15 they were evaluated in the first place and the result indicates that the reaction of 1a with 2a in the presence of 5 mol% of CuO nanoparticles at 110 °C for 24 h in toluene affords the production of 2,4,6-triphenyl-1,3,5-triazine (3aa) in 85% yield (Table 1, entry 1). However, the transformation of CuO nanoparticles into Cu(II) in the reaction limits their further uses. Therefore, different copper catalysts such as CuCl2, Cu(NO3)2, Cu(OAc)2, Cu(OTf)2 and Cu(acac)2 were detected, and Cu(OAc)2 stood out from the rest with 88% yield (Table 1, entries 2–6). Decreasing the amount of catalyst to 5% resulted in much lower yield (Table 1, entry 7). Increasing the amount of catalyst to 15% resulted in slightly higher yield (Table 1, entry 8). To our delight, we discovered that none of ligand wasnecessary (Table 1, entry 9). The yields of reactions performed in the presence of different bases such as NaHCO3, K2CO3 and Na2CO3 are essentially the same (Table 1, entries 9–11). Notably, base plays a vital role in the oxidative coupling reaction as the reaction cannot proceed without it (Table 1, entry 12). Na2CO3 was selected as base in the following due to its moderate basic strength and low-cost. Unfortunately, yields decreased remarkablly when DMF and DMSO were used as solvents, and a new product was detected (Table 1, entries 13 and 14). Lowering temperature to 80 oC, the yield reduced rapidly (Table 1, entries 15 and 16). With the reduction of reaction time to 18, 12 and 6 h, reduced yields of 80%, 70% and 55% were obtained, respectively (Table 1, entries 17–19). With the optimized reaction conditions presented in entry 11 of Table 1 in hand, a variety of primary alcohols and amidine hydrochlorides with different substituents were exploited as starting reactants to the synthesis of 1,3,5-triazine derivatives, and representative results are listed in Figure 2. Several functional groups, such as methoxy, chloro, fluoro and nitro were well-tolerated. No significant substitute effect was observed on aromatic alcohols, excellent yields were obtained for alcohols with both electron-donating and electron-withdrawing substituents on the para-position of aryl ring (Figure 2, 3ba, 3ea, 3ha, 3ia, 3la and 3ma). Relatively, low yields were obtained when alcohols were substituted with electron-withdrawing substituents such as Br and NO2, for example, the presence of a nitro group reduced yield to 46% (Figure 2, 3ja and 3ka). Besides, the steric hindrance has obvious effect on the reaction. For example, when methyl substituted benzyl alcohols were used, para and meta substituted substances gave higher yields than those with ortho substituents (Figure 2, 3ea, 3fa and 3ga). Apparent substitute effect was observed on amidine hydrochlorides. The reaction favored 1 with both 4-methylbenzamidine hydrochloride 2b and 4-(trifluoromethyl)benzamidine hydrochloride 2d, afforded 1,3,5-triazines in excellent yields (Figure 2, 3ab–3mb, 3ad, 3bd and 3id), while 2c with 4-Br on the phenyl ring led to 1,3,5-triazines in moderate yields (Figure 2, 3ic and 3lc). To our delight, good results were obtained as primary aliphatic alcohols such as methanol, ethanol, n-butyl alcohol and
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Cl Cl Cl N
N
N
N
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3aa, 88%
N
N
N
N
N N
N
N
3ba, 88%
3ca, 85%
3da, 55% CF3
a
N
N
N
N
N
N
3fa, 47%
3ha, 87%
N
N
N
N
N
3ia, 90%
3ja, 52%
F
Figure 2. Scope of the Synthesis of 1,3,5-Triazinesa
NO2
Br
N
Reaction conditions: benzamidine hydrochloride (1 mmol), benzyl alcohol (0.6 mmol), Cu(OAc)2 (10 mol %), Na2CO3 (1 mmol), toluene (2.5 mL) under reflux in air for 24 h.
N
3ga, 85%
O
N
N
N
N
3ea, 88%
N
N
N
N
isobutanol were tested (Figure 2, 3qa–3ta, 3qb and 3rb). In addition, isopropyl alcohol and sec-butyl alcohol were tested successively and the results showed that 3ra are the majorproduct, in accordance with the product from ethanol. However, the reaction of alkyl amidines such as acetamidine with benzylic alcohol failed to yield the desired product may be due to its boiling point was lower than our reaction temperature16. Furthermore, the reaction between benzamidine hydrochlorides (2a and 2b) and DMF (or DMSO) was investigated respectively (Scheme 2). The results showed that 3qa, 3qb and 2,4-bis(4-(trifluoromethyl)phenyl)-1,3,5-triazine were obtained in good to excellent yields via aerobic copper-catalyzed cyclization of amidines with DMF or DMSO, a one-carbon supplier. Comparing with Zhang’s report about CuI-catalyzed reaction of amidine with DMF in oxygen,17 more straight and simple route was presented.
N
N
N
3la, 92%
3ka, 46%
Cl N N
Cl N
N
N
N
N
N
N
3ma, 95%
3na, 90%
N
N
Cl
N
3oa, 97%
3pa, 97%
N
N
N
3ab, 87%
N N
N
N
N
N N
N
3bb, 96%
3eb, 86%
CF3
F
NH NH2 HCl +
N
N
N
N
N
N O S
R
N
N
3fb, 66%
3hb, 87%
3mb, 94%
R
O
N
N
N
N N
3ic, 50%
Br Br
3lc, 66%
N N
Br F3C
3ad, 98%
CF3
O
Cl
N
N
3bd, 88%
N N
N F3C
R
R N
Na2CO3 (2 equiv) air 110 oC R
R=H, 50% yield R=CH3, 46% yield R=CF3, 73% yield
N N R
R=H, 60% yield R=CH3, 63% yield R=CF3, 89% yield
Scheme 2. Formation of 1,3,5-Triazines from DMSO/DMF and Benzamidine hydrochlorides N
N
O
N N
Cu(OAc)2 H2O (10 mol%)
N NH2 HCl + N
Br
Na2CO3 (2 equiv) air 110 oC
NH
N
N
Cu(OAc)2 H2O (10 mol%)
CF3
F3C
3id, 75%
CF3
On the basis of great progress about metal catalyzed dehydrogenation formation of aldehyde from alcohol,18 a possible pathway for the formation of 2,4,6-trisubstituted-1,3,5-triazines was proposed (Scheme 3). Initially, aldehyde was formed by Cu(OAc)2 catalyzed alcohol oxidation in air.18a Then, the reaction of aldehyde and amidine was initiated and promoted by Cu(OAc)2 and air oxidation, giving rise to 1,3,5-triazines. The role of base is to neutralize hydrochloride of the amidine. The mechanism of the reaction is similar to that reported in the literature.8,9
Conclusions In summary, an efficient and simple method for the preparation
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Notes and references
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Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, People’s Republic of China. E-mail: [email protected] Tel: +86-553-3883513; fax: +86-553-3869310 † Electronic Supplementary Information (ESI) available: Catalyst characterization, analytic data, images of 1H and 13C NMR of all products and other electronic format. See DOI: 10.1039/b000000x/ 1
Scheme 3. Plausible Mechanism for synthesis of 1,3,5-Triazine of 1,3,5-triazine derivatives has been successfully developed based on direct oxidizing coupling reaction between benzamidine hydrochlorides and alcohols exploiting Cu(OAc)2 as catalyst. The obvious benefit of this approach is its tolerance to a broad range of both aromatic and fatty alcohols. In addition, the facile reaction atmosphere of air and no need of ligands make this approach highly practical for industrial manufacture. Further studies for the construction of diverse heterocyclic compounds relying on present strategy are ongoing in our lab.
Acknowledgements We gratefully appreciate the National Natural Science Foundation of China (NSFC Nos. 20972002 and 21272006) for financial support.
Experimental General information All starting materials and reagents were commercially available and used directly without further purification. All known products gave satisfactory analytical data by NMR spectra, which corresponding to the reported literature values. Unknown compounds were confirmed by HRMS additionally. NMR spectra were determined at room temperature on Bruker Avance-300 or Bruker Avance-500 at 300 MHz or 500 MHz with tetramethylsilane (TMS) as an internal standard. Chemical shifts are given in δ relative to TMS, the coupling constants J are given in Hz. High-resolution mass spectral (HRMS) were obtained using APCI, ESI or EI in positive mode. Typical experimental procedure for the synthesis of 3 A mixture of alcohol 1 (0.6 mmol), amidine hydrochloride 2 (1.0 mmol), NaCO3 (1.0 mmol, 1.0 equiv) and Cu(OAc)2 (10 mol %) was stirred in toluene (2.5 mL) under reflux in air for 24 h. The resulting mixture was cooled to room temperature and then extracted it for several times with EtOAc (10 mL) and brine (5 mL). The organic phases were combined and dried with anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography on silica
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This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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Synthesis of 1,3,5-Triazines via Cu(OAc)2-Catalyzed Aerobic Oxidative Coupling of Alcohols and Amidine hydrochlorides Qing You, Fei Wang, Chaoting Wu, Tianchao Shi, Dewen Min, Huajun Chen, Wu Zhang* Abstract: Cu(OAc)2 was found to be an efficient catalyst for dehydrogenative synthesis of 1,3,5-triazine derivatives via oxidative coupling reaction of amidine hydrochlorides and alcohols in air. Both aromatic and aliphatic alcohols can be involved in and thirty-three products were obtained with good to excellent yields. Moreover, the use of ligand, strong base and organic oxidant is unnecessary.
Introduction 1,3,5-triazines are very important skeletons of many biologically active compounds, such as herbicides, insecticides, fungicides, anticarcinogens and antivirals (Figure 1).1 In addition, they are also widely used as organic dyestuff, liquid crystal, flourescent brightener, electroluminescent materials, gas generating agent, solid propellant and pyrotechnics.2–3 In the past decades, a few approaches, including transition metal-catalyzed coupling reaction of halogenated 1,3,5-triazines,4 the cycotrimerizations of nitriles5 and multicomponent reaction of cyanamid, 1,2,4-triazole and triethyl orthoformate have been developed for the synthesis of 1,3,5-triazine derivatives.6 Alternatively, these compounds were also obtained through the pathways based on the use of available amidines as substrates, for example, domino heterocyclization of isothiocyanates with aryl amidines,7 cesium carbonate-promoted cyclodehydrogenation of amidine hydrochloride with aromatic aldehyde.8 However, these methods suffer from limitations of operating difficulties or tough reaction conditions involving strong base, microwave, noble metal catalyst and organic oxidant. Recently, Zhang et al. reported new strategies for the synthesis of 2,4,6-triaryl-1,3,5-triazines based on ruthenium-catalyzed reaction of aryl methanols and amidines.9 The disadvantages of the strategy lies in noble metal ruthenium-based catalysts and limitation of substrate suitability. As a result, more robust and efficient method for the synthesis of 1,3,5-triazine is still extremely in demand, especially involving the synthesis carried out under gentle conditions with inexpensive catalysts. Copper catalysts with features of low cost and environmental friendliness were frequently utilized to synthesize novel heterocyclic compounds.10–12 For example, Nagasawa et al. have reported that Cu(OTf)2 exhibited impressive catalytic ability in intramolecular oxidative C–N coupling reaction and
Figure 1. Parts of Products of 1,3,5-Triazines Previous report:
This work:
Scheme 1. Synthesis of 1,3,5-Triazines intermolecular amino cyclization.13 Our previous findings also showed that copper-based catalysts are attractive in the catalytic formation of carbon–heteroatom bonds (Scheme 1).14 Herein, we report the synthesis of 1,3,5-triazine derivatives directly by oxidative coupling of amidine hydrochlorides and alcohols in air with Cu(OAc)2 as a catalyst. Compared with the relevant reported reactions for the synthesis of 1,3,5-triazine derivative,8,9 our method is more efficient as evidenced by the fact that both aryl methanols and alkyl alcohols are utilizable as starting reactants in the oxidative coupling reaction.
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Table 1. Optimization of the Reaction Conditionsa
entry
catalyst (mol%)
ligand
solvent
base
1 2
nanoCuO (5) CuCl2 (10)
Phen Phen
toluene toluene
K2CO3 K2CO3
yield (%)b 85 75
3
Cu(NO3)2 (10) Cu(OAc)2 (10) Cu(acac)2 (10) Cu(OTf)2 (10) Cu(OAc)2 (5) Cu(OAc)2 (15) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10) Cu(OAc)2 (10)
Phen
toluene
K2CO3
70
Phen
toluene
K2CO3
88
Phen
toluene
K2CO3
80
Phen Phen Phen
toluene toluene toluene
K2CO3 K2CO3 K2CO3
85 60 89
toluene
K2CO3
88
toluene
NaHCO3
87
_
toluene
Na2CO3
88
_
toluene
_
_
_
DMF
Na2CO3
45
_
DMSO
Na2CO3
55
_
toluene
Na2CO3
30
_
toluene
Na2CO3
60
_
toluene
Na2CO3
55
_
toluene
Na2CO3
70
_
toluene
Na2CO3
80
4 5 6 7 8 9 10 11 12 13 14 15c 16d 17e 18f 19g
_ _
a Reaction conditions: benzamidine hydrochloride (1 mmol), benzyl alcohol (0.6 mmol), Cu(OAc)2 (10 mol %), Na2CO3 (1 mmol), toluene (2.5 mL) under reflux in air for 24 h. bIsolated yield. Reaction temperature: c80 oC, d100 oC. Reaction time: e6 h, f12 h, g18 h.
Results and discussion We started with the optimization of the oxidative coupling conditions exploiting benzyl alcohol (1a) and benzamidine hydrochloride (2a) as the model substrates. The results obtained
DOI: 10.1039/C5OB00724K
from screening of the copper catalysts, ligands and solvents are summarized in Table 1. Given efficient catalytic activity and good recyclability of CuO nanoparticles,15 they were evaluated in the first place and the result indicates that the reaction of 1a with 2a in the presence of 5 mol% of CuO nanoparticles at 110 °C for 24 h in toluene affords the production of 2,4,6-triphenyl-1,3,5-triazine (3aa) in 85% yield (Table 1, entry 1). However, the transformation of CuO nanoparticles into Cu(II) in the reaction limits their further uses. Therefore, different copper catalysts such as CuCl2, Cu(NO3)2, Cu(OAc)2, Cu(OTf)2 and Cu(acac)2 were detected, and Cu(OAc)2 stood out from the rest with 88% yield (Table 1, entries 2–6). Decreasing the amount of catalyst to 5% resulted in much lower yield (Table 1, entry 7). Increasing the amount of catalyst to 15% resulted in slightly higher yield (Table 1, entry 8). To our delight, we discovered that none of ligand wasnecessary (Table 1, entry 9). The yields of reactions performed in the presence of different bases such as NaHCO3, K2CO3 and Na2CO3 are essentially the same (Table 1, entries 9–11). Notably, base plays a vital role in the oxidative coupling reaction as the reaction cannot proceed without it (Table 1, entry 12). Na2CO3 was selected as base in the following due to its moderate basic strength and low-cost. Unfortunately, yields decreased remarkablly when DMF and DMSO were used as solvents, and a new product was detected (Table 1, entries 13 and 14). Lowering temperature to 80 oC, the yield reduced rapidly (Table 1, entries 15 and 16). With the reduction of reaction time to 18, 12 and 6 h, reduced yields of 80%, 70% and 55% were obtained, respectively (Table 1, entries 17–19). With the optimized reaction conditions presented in entry 11 of Table 1 in hand, a variety of primary alcohols and amidine hydrochlorides with different substituents were exploited as starting reactants to the synthesis of 1,3,5-triazine derivatives, and representative results are listed in Figure 2. Several functional groups, such as methoxy, chloro, fluoro and nitro were well-tolerated. No significant substitute effect was observed on aromatic alcohols, excellent yields were obtained for alcohols with both electron-donating and electron-withdrawing substituents on the para-position of aryl ring (Figure 2, 3ba, 3ea, 3ha, 3ia, 3la and 3ma). Relatively, low yields were obtained when alcohols were substituted with electron-withdrawing substituents such as Br and NO2, for example, the presence of a nitro group reduced yield to 46% (Figure 2, 3ja and 3ka). Besides, the steric hindrance has obvious effect on the reaction. For example, when methyl substituted benzyl alcohols were used, para and meta substituted substances gave higher yields than those with ortho substituents (Figure 2, 3ea, 3fa and 3ga). Apparent substitute effect was observed on amidine hydrochlorides. The reaction favored 1 with both 4-methylbenzamidine hydrochloride 2b and 4-(trifluoromethyl)benzamidine hydrochloride 2d, afforded 1,3,5-triazines in excellent yields (Figure 2, 3ab–3mb, 3ad, 3bd and 3id), while 2c with 4-Br on the phenyl ring led to 1,3,5-triazines in moderate yields (Figure 2, 3ic and 3lc). To our delight, good results were obtained as primary aliphatic alcohols such as methanol, ethanol, n-butyl alcohol and
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Cl Cl Cl N
N
N
N
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3aa, 88%
N
N
N
N
N N
N
N
3ba, 88%
3ca, 85%
3da, 55% CF3
a
N
N
N
N
N
N
3fa, 47%
3ha, 87%
N
N
N
N
N
3ia, 90%
3ja, 52%
F
Figure 2. Scope of the Synthesis of 1,3,5-Triazinesa
NO2
Br
N
Reaction conditions: benzamidine hydrochloride (1 mmol), benzyl alcohol (0.6 mmol), Cu(OAc)2 (10 mol %), Na2CO3 (1 mmol), toluene (2.5 mL) under reflux in air for 24 h.
N
3ga, 85%
O
N
N
N
N
3ea, 88%
N
N
N
N
isobutanol were tested (Figure 2, 3qa–3ta, 3qb and 3rb). In addition, isopropyl alcohol and sec-butyl alcohol were tested successively and the results showed that 3ra are the majorproduct, in accordance with the product from ethanol. However, the reaction of alkyl amidines such as acetamidine with benzylic alcohol failed to yield the desired product may be due to its boiling point was lower than our reaction temperature16. Furthermore, the reaction between benzamidine hydrochlorides (2a and 2b) and DMF (or DMSO) was investigated respectively (Scheme 2). The results showed that 3qa, 3qb and 2,4-bis(4-(trifluoromethyl)phenyl)-1,3,5-triazine were obtained in good to excellent yields via aerobic copper-catalyzed cyclization of amidines with DMF or DMSO, a one-carbon supplier. Comparing with Zhang’s report about CuI-catalyzed reaction of amidine with DMF in oxygen,17 more straight and simple route was presented.
N
N
N
3la, 92%
3ka, 46%
Cl N N
Cl N
N
N
N
N
N
N
3ma, 95%
3na, 90%
N
N
Cl
N
3oa, 97%
3pa, 97%
N
N
N
3ab, 87%
N N
N
N
N
N N
N
3bb, 96%
3eb, 86%
CF3
F
NH NH2 HCl +
N
N
N
N
N
N O S
R
N
N
3fb, 66%
3hb, 87%
3mb, 94%
R
O
N
N
N
N N
3ic, 50%
Br Br
3lc, 66%
N N
Br F3C
3ad, 98%
CF3
O
Cl
N
N
3bd, 88%
N N
N F3C
R
R N
Na2CO3 (2 equiv) air 110 oC R
R=H, 50% yield R=CH3, 46% yield R=CF3, 73% yield
N N R
R=H, 60% yield R=CH3, 63% yield R=CF3, 89% yield
Scheme 2. Formation of 1,3,5-Triazines from DMSO/DMF and Benzamidine hydrochlorides N
N
O
N N
Cu(OAc)2 H2O (10 mol%)
N NH2 HCl + N
Br
Na2CO3 (2 equiv) air 110 oC
NH
N
N
Cu(OAc)2 H2O (10 mol%)
CF3
F3C
3id, 75%
CF3
On the basis of great progress about metal catalyzed dehydrogenation formation of aldehyde from alcohol,18 a possible pathway for the formation of 2,4,6-trisubstituted-1,3,5-triazines was proposed (Scheme 3). Initially, aldehyde was formed by Cu(OAc)2 catalyzed alcohol oxidation in air.18a Then, the reaction of aldehyde and amidine was initiated and promoted by Cu(OAc)2 and air oxidation, giving rise to 1,3,5-triazines. The role of base is to neutralize hydrochloride of the amidine. The mechanism of the reaction is similar to that reported in the literature.8,9
Conclusions In summary, an efficient and simple method for the preparation
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Notes and references
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Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, People’s Republic of China. E-mail: [email protected] Tel: +86-553-3883513; fax: +86-553-3869310 † Electronic Supplementary Information (ESI) available: Catalyst characterization, analytic data, images of 1H and 13C NMR of all products and other electronic format. See DOI: 10.1039/b000000x/ 1
Scheme 3. Plausible Mechanism for synthesis of 1,3,5-Triazine of 1,3,5-triazine derivatives has been successfully developed based on direct oxidizing coupling reaction between benzamidine hydrochlorides and alcohols exploiting Cu(OAc)2 as catalyst. The obvious benefit of this approach is its tolerance to a broad range of both aromatic and fatty alcohols. In addition, the facile reaction atmosphere of air and no need of ligands make this approach highly practical for industrial manufacture. Further studies for the construction of diverse heterocyclic compounds relying on present strategy are ongoing in our lab.
Acknowledgements We gratefully appreciate the National Natural Science Foundation of China (NSFC Nos. 20972002 and 21272006) for financial support.
Experimental General information All starting materials and reagents were commercially available and used directly without further purification. All known products gave satisfactory analytical data by NMR spectra, which corresponding to the reported literature values. Unknown compounds were confirmed by HRMS additionally. NMR spectra were determined at room temperature on Bruker Avance-300 or Bruker Avance-500 at 300 MHz or 500 MHz with tetramethylsilane (TMS) as an internal standard. Chemical shifts are given in δ relative to TMS, the coupling constants J are given in Hz. High-resolution mass spectral (HRMS) were obtained using APCI, ESI or EI in positive mode. Typical experimental procedure for the synthesis of 3 A mixture of alcohol 1 (0.6 mmol), amidine hydrochloride 2 (1.0 mmol), NaCO3 (1.0 mmol, 1.0 equiv) and Cu(OAc)2 (10 mol %) was stirred in toluene (2.5 mL) under reflux in air for 24 h. The resulting mixture was cooled to room temperature and then extracted it for several times with EtOAc (10 mL) and brine (5 mL). The organic phases were combined and dried with anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography on silica
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